Gefitinib Receives European Licence For The Treatment Of Lung Cancer For Patients With EGFR Activating Mutation Positive Tumours

Main Category: Lung Cancer
Also Included In: Respiratory / Asthma;  Cancer / Oncology
Article Date: 02 Jul 2009 - 3:00 PDT

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AstraZeneca announced that it has received a licence by the European Medicines Agency (EMEA) for its oral targeted anti-cancer drug, gefitinib, for EGFR (epidermal growth factor receptor-tyrosine kinase) activating mutation positive patients with Non Small Cell Lung Cancer (NSCLC). NSCLC is the most common type of lung cancer and accounts for 80% of all lung cancer cases. [1] The licence means that for the first time, thousands [2] of patients undergoing first line treatment of NSCLC in the UK may benefit from a more effective, [3] oral alternative to doublet chemotherapy (UK standard of care) without many of the side effects associated with chemotherapy. [3]

Gefitinib is licensed for use in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (epidermal growth factor receptor-tyrosine kinase), in all lines of therapy. [4]

Gefitinib is the only oral targeted therapy available for first line use, having demonstrated superior efficacy vs. doublet chemotherapy for patients with a specific genetic mutation of their tumours (EGFR activating mutation positive tumours) and is one of just a handful of anti cancer drugs already available to target only those patients most likely to benefit.

EGFR mutation status of a patient's tumour is a strong predictor of benefit with gefitinib. [3,5] When compared to standard chemotherapy, not only did significantly more patients with EGFR mutation positive tumours respond to treatment with gefitinib (71.2% v 47.3%, p=0.0001) but they also lived significantly longer without their cancer growing (progression free survival) (median PFS 9.5 months vs 6.3 months; HR 0.48, 95% CI 0.36 to 0.64, p<0.0001). [3] In a pivotal phase III randomized study, the data showed that in the first line treatment setting 71.2% of EGFR mutation positive patients respond to gefitinib compared to 47.3% in the doublet chemotherapy arm. [3] Data from a separate phase III study reported at ASCO 2009, further emphasize and confirm the significant efficacy advantages of gefitinib when targeting this group of mutation positive patients. [5]

Professor Nick Thatcher, Professor in Medical Oncology at the Christie Hospital in Manchester said: "This is a new targeted therapy approach in every sense of the word and a major step forward to treat non small cell lung cancer patients. For the first time in NSCLC, there is a medicine available that is more effective than chemotherapy and without many of the known side effects of chemotherapy. What's really exciting is that we know which patients may benefit from this medicine, meaning NHS resources can be optimised and patients and doctors can be much more confident about the treatment outcomes."

EGFR mutation testing is not a common practice in the UK, however capabilities are available for this type of genetic testing. In advance of NICE appraisal for gefitinib (May 2010), AstraZeneca is working with the NHS to ensure EGFR testing is available, so that NSCLC patients who may benefit more from the oral targeted medicine gefitinib than the current standard of care (doublet chemotherapy) can be identified and to ensure best use of NHS resources.

The licence is based on data from two pivotal Phase III studies, IPASS and INTEREST. In IPASS, gefitinib significantly delayed cancer progression (median PFS 9.5 months vs 6.3 months; HR 0.48, 95% CI 0.36 to 0.64, p<0.0001) and improved tumour shrinkage for NSCLC patients with the activating mutation of EGFR-TK compared with doublet chemotherapy (71.2% v 47.3%, p=0.0001), [3] while in INTEREST, gefitinib demonstrated equivalent survival to chemotherapy for patients who progressed on or following chemotherapy. [6]

In both trials gefitinib demonstrated a better tolerability profile than chemotherapy as well as quality of life benefits. [3,6]

Unlike chemotherapy, gefitinib, which is taken orally as a once-a-day 250 mg tablet, has been designed to target cancer cells while sparing healthy cells, which could help reduce the side effects seen with chemotherapy. The most commonly seen side-effects of gefitinib are mild-to-moderate rash and diarrhoea. [3,4,6]

In the UK of 25,000 patients with advanced NSCLC only 65% (approx. 16,000) receive treatment, usually chemotherapy. [2] Now that an oral, targeted treatment without many of the side effects of chemotherapy is available for mutation positive patients more NSCLC patients can be considered for active treatment.

About IPASS [3]

IPASS was an open label, randomised, parallel-group study that assessed the efficacy, safety and tolerability of gefitinib versus carboplatin/paclitaxel as first-line treatment in a clinically selected population of patients from Asia. The study enrolled 1,217 patients in Asia with advanced NSCLC who had not received prior chemotherapy for advanced disease, whose tumours were of adenocarcinoma histology and who had either never smoked, or were former light smokers (ceased smoking at least 15 years ago and <= 10 pack-years exposure).

The IPASS study exceeded its primary objective, demonstrating superior progression-free survival (PFS, the time a patient lives without their cancer progressing). PFS was significantly longer for gefitinib than doublet chemotherapy in patients with EGFR mutation positive tumours (median PFS 9.5 months vs 6.3 months; HR 0.48, 95% CI 0.36 to 0.64, p<0.0001), and significantly longer for doublet chemotherapy than gefitinib in patients with EGFR mutation negative tumours (median PFS 5.5 months vs 1.5 months; HR 2.85, 95% CI 2.05 to 3.98, p<0.0001).

For secondary endpoints, objective response rate (ORR) was superior for gefitinib in the overall population (43% vs. 32% for gefitinib and carboplatin/paclitaxel respectively; p=0.0001); for patients with EGFR mutation positive tumours, ORR was superior for gefitinib (71.2% vs 47.3%, p=0.0001), and for patients with EGFR mutation negative tumours, ORR was superior for chemotherapy (1.1% vs 23.4% , p=0.0013).

The safety profile of gefitinib was generally consistent with its prescribing information, previous gefitinib studies in the relapsed setting, and underlying disease. The most commonly reported adverse events with gefitinib are mild to moderate rash and diarrhoea. There were improved tolerability and quality of life benefits for gefitinib compared to carboplatin/paclitaxel doublet chemotherapy in clinically selected first-line patients in Asia.

About INTEREST [6]

The INTEREST (Iressa Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study was a randomised, open-label, parallel-group, Phase III trial evaluating survival with gefitinib versus docetaxel in 1,466 patients with locally advanced or metastatic recurrent NSCLC who had previously received platinum-based chemotherapy. The primary endpoint of INTEREST was OS, with the objective of demonstrating that gefitinib was non-inferior to docetaxel chemotherapy.

The INTEREST study met its primary objective, demonstrating equivalent overall survival (OS) and significant quality of life benefits for gefitinib compared to standard chemotherapy (docetaxel) in the pre-treated setting.[6] A retrospective analysis showed a significant improvement in PFS and ORR for gefitinib over docetaxel in patients with EGFR sensitising mutation positive tumours. [7]

About gefitinib

- Mode of Action: gefitinib is an EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor), which targets and blocks the activity of the EGFR-TK, an enzyme that regulates intracellular signalling pathways implicated in cancer cell proliferation and survival. Growth factor signalling has been identified as a key driver of tumour growth and spread in a wide range of cancers

- Gefitinib (250 mg) is a once-daily oral therapy.

- Gefitinib is licensed in 36 countries for the treatment of patients with locally advanced or metastatic NSCLC who have previously received chemotherapy.

About EGFR mutations

- EGFR mutations are changes in the DNA sequence of the EGFR gene which codes for the EGFR protein, leading to the production of mutated EGFR, rather than wild-type (non-mutated) EGFR. Tumour cells with mutated EGFR seem to be drawn to signalling via the EGFR pathway.

- The EGFR receptor has been shown to play an important role in NSCLC. Some patients will exhibit mutations within the gene of this receptor.

- A mutation in the EGFR is a characteristic occurring in approximately 12.7% [8] of lung cancers in non-Asian patients.

About lung cancer in the UK

- Lung cancer is the second most commonly diagnosed cancer in the UK. Each year more than 38,000 people are diagnosed with lung cancer in the UK. [9]

- There are several different types of lung cancer, NSCLC being the most common. 80% of lung cancer patients are diagnosed with NSCLC. [1]

- The UK has one of the worst lung cancer survival rates in Europe, 8.6% survival at 5-years in England compared with a mean of 12.6% across Europe. [10]

About gefitinib and NICE

AstraZeneca will submit gefitinib to NICE for review in September 2009

References

[1] Cancer Research UK, UK Lung Cancer incidence statistics. http://info.cancerresearchuk.org/cancerstats/types/lung/incidence/. Date accessed 19.03.09

[2] AstraZeneca Data on File (DOF) IRE/014/MAY09

[3] Mok T. Phase III, Randomised, Open-Label, First-Line Study Of Gefitinib Vs Carboplatin/Paclitaxel (C/P) Clinically Selected Patients With Advanced Non-Small-Cell Lung Cancer (IPASS), Presentation at ESMO 2008

[4] Gefitinib (IRESSA [TM]) SmPC. http://www.Medicines.Org.uk

[5] Kobayashi et al. First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations: A phase III study (002) by North East Japan Gefitinib Study Group. Poster presented at ASCO 2009. (abs. 8016)

[6] Kim, ES et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372: 1809-18

[7] Douillard, J. et al. Molecular and clinical subgroup analyses from a phase III trial comparing gefitinib with docetaxel in previously treated non-small cell lung cancer (INTEREST). Presentation at ASCO 2008.

[8] AstraZeneca Data on file (DOF) IRE/013/APR09

[9] Cancer Research UK. Date accessed 17.03.09

[10] Berrino F, De Angelis R, Sant M et al. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995-1999: results of the EUROCARE-4 study Lancet Oncology 2007; 8:773-783

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AstraZeneca

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